title: The JNK inhibitor, SP600125, potentiates the glial response and cell death induced by methamphetamine in the mouse striatum.
abstract: This study investigates the effect of the selective Jun NH2-terminal kinase 1/2 (JNK1/2) inhibitor, (SP600125) on the striatal dopamine nerve terminal loss and on the increased interleukin-15 (IL-15) expression and glial response induced by methamphetamine (METH). Mice were given repeated low doses of METH (4 mg/kg, i.p., three times separated by 3 h) and killed 24 h or 7 d after the last dose. SP600125 (30 mg/kg, i.p) was administered 30 min before the last METH injection. Results indicate that METH produced dopaminergic axonal neurotoxicity reflected as a marked decrease in the striatal density of tyrosine hydroxylase-immunoreactive (TH-ir) fibres and dopamine transporter-immunoreactivity (DAT-ir) 24 h after dosing. These effects were not modified by SP600125. This compound also failed to prevent the long-term loss of dopamine levels and DAT observed 7 d following METH injection. Nevertheless, SP600125 potentiated METH-induced striatal cell loss reflected by an increase in Fluoro-Jade immunostaining, cleaved capase-3 immunoreactivity and the number of terminal deoxyncleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells. In line with a deleterious effect of JNK1/2 inhibition, SP600125 increased the astroglial and microglial response induced by METH and interfered with drug-induced IL-15 expression. Together these data indicate that, not only does SP600125 fail to protect against the dopaminergic damage induced by METH but also, in fact, it potentiates the glial response and the non-dopaminergic striatal cell loss caused by the drug.
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Urrutia
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Granado
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Gutierrez-Lopez
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: O'Shea
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Colado
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004357:Drug Synergism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding / Q000502:physiology
chemical_list: D000873:Anthracenes; C432165:pyrazolanthrone; D008694:Methamphetamine; D048031:JNK Mitogen-Activated Protein Kinases